Since 1998, the National Institutes of Health has funded 5 randomized controlled trials (RCTs) for primary and secondary prevention of strokes in children with sickle cell anemia (SCA). In a systematic fashion, these trials have significantly advanced the care of children with SCA. In the absence of an RCT, clinicians are often compelled to make decisions at the bedside, based on experience, observational studies, and principles of hematology. We will provide an initial example that describes how a team-based, learning collaborative developed a multisite standard care protocol with a low budget (<$10000 per year) to overcome the intrinsic limitations of advancing the care of neurologic complications in sickle cell disease (SCD). The critical components of this approach include: (1) regular meetings with the multidisciplinary team from multiple sites; (2) consensus regarding the best evidence-based neurologic management in multiple SCD centers; (3) an Institutional Review Board-approved protocol based on consensus standard care; (4) minimizing and ensuring accurate data collection; and most importantly, (5) a spirit of collaboration to improve the care of individuals with SCD. Four common neurologic problems and strategies for management in children and adults with SCD will be discussed: (1) secondary stroke prevention in high-income countries; (2) primary stroke prevention in low- and middle-income countries (LMICs); (3) poor academic performance in students; and (4) cognitive disability in adults. With a commitment to a team-based learning collaborative, incremental advances are possible for the neurologic care of children and adults with SCD.